UNASSIGNED: Breast cancer (BC) is the most common non-skin cancer affecting women but is extremely uncommon in the adolescent population. Genetic inheritance has been linked to <10% of BCs. CHEK2 is an uncommon genetic variant with a reported incidence of 0.3-1.6% in the general population and 4.9-5.7% in those with a family history of BC. Commonly, this mutation presents in females of European descent and is rare in North America.
UNASSIGNED: A 19-year-old Caucasian female presented with breast pain and mass. She had an extensive family history of cancer, as well as a known CHEK2 gene mutation in 2 of her paternal aunts. Ultrasound and MRI confirmed a 4.5-cm mass with an enlarged right axillary lymph node. Image guided biopsy of the breast mass showed ER/PR-positive grade 1 invasive mucinous ductal cancer. Genetic testing confirmed an isolated CHEK2 mutation. After discussion by a multidisciplinary tumor board, the patient deferred bilateral mastectomy and underwent a right mastectomy with sentinel-lymph-node biopsy and immediate tissue-expander reconstruction. Final pathology confirmed ER/PR-positive Stage 1A (pT2 pN0 M0) invasive mucinous carcinoma. Chemotherapy was not recommended.
UNASSIGNED: Malignant adolescent breast masses are relatively rare and CHEK2 does not typically present at younger than 20 years of age. While there are many different differential diagnoses when evaluating an adolescent with a breast mass, we wish to increase providers\' suspicion of malignancy, specifically in those individuals who have a strong family history of BC and the CHEK2*1100delC mutation.

BACKGROUND: While BRCA1/2 gene mutational spectrum and clinical features are widely studied, there is limited data on breast cancer-predisposing non-BRCA pathogenic/likely pathogenic variants (PV/LPVs) in the Baltic states region. According to previous studies, CHEK2 is the most frequent moderate-risk breast cancer predisposition gene. The study aimed to analyse the frequency and mutational spectrum of CHEK2 PV/LPVs in the Baltic states region and perform a literature review on the subject.
METHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords \'CHEK2\', \'breast cancer\', \'Estonia\', \'Lithuania\', \'Latvia\', \'Poland\', \'Belarus\' and \'Russia\'.
RESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus.
CONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant\'s pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.

Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry.
We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19.
review of the literature discusses that the combined risk is 12.36%-20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry.
We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.

The association between the checkpoint kinase 2*1100delC (CHEK2*1100delC) and breast cancer has been extensively explored.
In light of the recent publication of studies on these specific findings, particularly regarding male patients with breast cancer, we performed an updated meta-analysis to investigate a more reliable estimate.
This meta-analysis included 26 published studies selected in a search of electronic databases up to January 2018, including 118,735 breast cancer cases and 195,807 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between 1100delC and breast cancer.
Meta-analysis results suggested that 1100delC contributed to an increased breast cancer risk in overall populations (OR 2.89; 95% CI 2.63-3.16). Subgroup analysis found ORs of 3.13 (95% CI 1.94-5.07) for male breast cancer, 2.88 (95% CI 2.63-3.16) for female breast cancer, 2.87 (95% CI 1.85-4.47) for early-onset breast cancer, 2.92 (95% CI 2.65-3.22) for invasive breast cancer, and 3.21 (95% CI 2.41-4.29) for familial breast cancer. The sensitivity analysis suggested that results of this meta-analysis were generally robust.
CHEK2*1100delC is associated with an increased risk of both female and male breast cancer.

Breast cancer (BC) is the most frequent malignancy in both pre- and postmenopausal women. However, it is exceedingly rare in very young patients, and especially in adolescents. Herein, we report a case of an 18-year-old female diagnosed with invasive BC. The proband had been found to be negative for BC in close family members. A common BC genetic screening test for the Polish population did not detect any known founder mutations in the BRCA1 gene. Further evaluation identified a p.Ile157Thr (I157T) mutation in the CHEK2 gene, a p.Ala1991Val (A1991V) variant of unknown significance in the BRCA2 gene, p.Lys751Gln (K751Q) variant in the XPD (ERCC2) gene, and a homozygous p.Glu1008Ter (E1008*) mutation in the NOD2 gene. No other mutation had been found by next generation sequencing in major BC high-risk susceptibility genes BRCA1, BRCA2, as well as 92 other genes. To date, all these found alterations have been considered as low to moderate risk factors in the general population and moderate risk factors in younger women (<35 years of age). There are no previous articles relating low and moderate risk gene mutations to very young onset (below 20 years) BC with a fatal outcome. In our patient, a possible cumulative or synergistic risk effect for these 4 alterations, and a mutation in the NOD2 gene in particular, of which both presumably healthy parents were found to be carriers, is suggested.

BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) gene I157T variant may be associated with an increased risk of colorectal cancer, but it is unclear whether the evidence is sufficient to recommend testing for the mutation in clinical practice.
METHODS: We systematically searched PubMed, EMBASES, Elsevier and Springer for relevant articles before Apr 2012. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a fixed-effects or random-effects models with Review Manager 5.0 software.
RESULTS: A total of seven studies including 4,029 cases and 13,844 controls based on the search criteria were included for analysis. A significant association of the CHEK2 I157T C variant with unselected CRC was found (OR=1.61, 95% CI=1.40-1.87, P<0.001). We also found a significant association with sporadic CRC (OR=1.48, 95% CI=1.23-1.77, P<0.001) and separately with familial CRC (OR=1.97, 95% CI=1.41-2.74, P<0.001).
CONCLUSIONS: This meta-analysis demonstrates that the CHEK2 I157T variant may be another important CRC-predisposing gene, which increases CRC risk, especially in familial CRC.

BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) gene I157T variant may be associated with an increased risk of breast cancer, but it is unclear whether the evidence is sufficient to recommend testing for the mutation in clinical practice.
METHODS: We systematically searched PubMed, Embase, Elsevier and Springer for relevant articles published before Nov 2011. Summary odds ratio (OR) and 95% confidence interval (95% CI) incidence rates were calculated using a random-effects model with STATA (version 10.0) software.
RESULTS: A total of fifteen case-control studies, including 19,621 cases and 27,001 controls based on the search criteria, were included for analysis. A significant association was found between carrying the CHEK2 I157T variant and increased risk of unselected breast cancer (OR = 1.48, 95% CI = 1.31-1.66, P < 0.0001), familial breast cancer (OR = 1.48, 95% CI = 1.16-1.89, P < 0.0001), and early-onset breast cancer (OR = 1.47, 95% CI = 1.29-1.66, P < 0.0001). We found an even stronger significant association between the CHEK2 I157T C variant and increased risk of lobular type breast tumors (OR = 4.17, 95% CI = 2.89-6.03, P < 0.0001).
CONCLUSIONS: Our research indicates that the CHEK2 I157T variant may be another important genetic mutation which increases risk of breast cancer, especially the lobular type.

BACKGROUND: Cells that suffer DNA damage activate the checkpoint kinases CHK1 and CHK2, which signal to initiate repair processes, limit cell-cycle progression and prevent cell replication, until the damaged DNA is repaired. Due to their potential application as novel anticancer therapies, inhibitors of CHK1 and CHK2 have become the focus of numerous drug discovery projects.
METHODS: This patent review examines the chemical structures and biological activities of recently reported CHK1 and CHK2 inhibitors. The chemical abstract and patent databases SciFinder and esp@cenet were used to locate patent applications that were published between September 2008 and December 2010, claiming chemical structures for use as CHK1 or CHK2 inhibitors.
CONCLUSIONS: This is an exciting time for checkpoint kinase inhibitors, with several currently in Phase I or II clinical trials. Many of the CHK1 inhibitors contained within this patent review have shown preclinical efficacy in combination with DNA-damaging chemotherapies. CHK1 inhibitors have recently been demonstrated to be efficacious as single agents in preclinical models of tumors with constitutive activation of CHK1 or high intrinsic DNA damage due to replication stress. The level of newly published patent applications covering CHK1 and CHK2 inhibitors remains high and a diverse range of scaffolds has been claimed.

BACKGROUND: The checkpoint kinases, Chk1 and Chk2 are Ser/Thr protein kinases, which function as key regulatory kinases in cellular DNA damage response pathways limiting cell-cycle progression in the presence of DNA damage. The development of checkpoint kinase inhibitors for the treatment of cancer has been a major objective in drug discovery over the past decade, as evidenced by three checkpoint kinase inhibitors entering clinic trials since late 2005.
OBJECTIVE: This review describes and discusses the most recent inhibitors of checkpoint kinases Chk1 and Chk2, as reported in the patent literature, including an evaluation of chemical structure and biological activity.
METHODS: Using a variety of approaches, we searched and analyzed all patent applications claiming chemical matter in which Chk1 or Chk2 were stated as targets of inhibition from January 2006 through August 2008.
CONCLUSIONS: A large number of chemically diverse Chk1 and Chk2 kinase inhibitors have appeared in the recent patent literature. Common structural motifs of the checkpoint kinase inhibitors were identified. There are currently three checkpoint kinase inhibitors in clinical development, a continuing effort by the pharmaceutical industry to identify novel scaffolds for checkpoint kinase inhibition.